Biofilms are thought to cause a significant amount of all human microbial infections, according to the Centers for Disease Control and Prevention [1]. Nosocomial infections are the fourth leading cause of death in the U.S. with >2 million cases annually (or ~10% of American hospital patients). About 60% of all such infections are associated with an implanted medical device causing >$4.5 billion medical costs in 1992 [2] and ~80,000 deaths annually [3]. Well-recognized infections involving biofilms include bacterial endocarditis, cystic fibrosis lung infections, deep wound healing, the current dental caries epidemic, periodontal disease, vaginosis, urinary tract infections, and chronic middle ear infections. Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth leading to resorption of alveolar bone and eventual tooth loss. The disease is a major public health problem in all societies and is estimated to affect up to 15% of the adult dentate population, with severe forms affecting 5 6%. The development and progression of chronic periodontitis has been associated with specific Gram-negative bacteria in subgingival plaque. Persistence of Porphyromonas gingivalis in subgingival plaque from periodontitis patients after treatment (scaling and root planing) has been reported to be significantly associated with progressive alveolar bone loss. Moreover, an increase in P. gingivalis cell numbers in subgingival plaque has been shown to correlate with disease severity as measured by attachment loss, periodontal pocket depth, and bleeding on probing. Guided tissue regeneration (GTR) techniques are increasingly being used for the treatment of periodontal defects, or in conjunction with dental implant procedures. Several studies have shown that optimal tissue regeneration cannot be expected for barrier membranes placed in sites infected by periodontopathic microorganisms. A prerequisite for tissue regeneration success is therefore an infection-free healing process. This proposal seeks to develop biomaterials that promote a life-long immunity protection against infections of long-term indwelling biomedical devices. Our goal, with NIDCR support, is to develop tissue regenerative biomaterials that will also provide a short- term defense and long-term immune response to specific bacterial colonization. For short-term immediate defense, model biomaterials will release fusion protein complexes - artificial opsonins - designed to enhance the coupling of pathogenic oral bacteria to monocyte-macrophage (MX);thus promoting phagocytosis. For long-term protection, the biomaterial will transfect antigen-presenting cells (specifically dendritic cells - DCs) to produce T- and B-cell memory and antibody expression, and potentially stimulate direct native killer T-cell responses. This two-tiered biological approach to preventing biomaterials infections will first be established in the model microbial system of Porphyromonas gingivalis (PG) colonization of periodontal tissue guided regeneration systems. PUBLIC HEALTH RELEVANCE: Nosocomial infections are the fourth leading cause of death in the U.S. with ~60% of such infections being associated with an implanted medical device. Our goal is to develop tissue regenerative biomaterials that will also provide a short-term defense and life long immune response to specific bacterial infections